RESUMEN
We investigated the regulatory role of miR-181b-5p in neutrophilic asthma and its mechanisms by targeting DEK. DEK, matrix metalloproteinase (MMP)-2, and MMP-9 were overexpressed and the miR-181b-5p was decreased in mice with neutrophilic asthma. DEK was a direct target of miR-181b-5p. In mouse model, miR-181b-5p agomir had an inhibitory effect on airway inflammation and remodeling. miR-181b-5p inhibited DEK/p-GSK-3ßSer9/ß-catenin/MMP-9 pathway activation by regulating Wnt ligands in BEAS-2B and 16HBE cells. The ability of supernatants from human bronchial epithelial cells (hBECs) co-stimulated with CXCL8 (IL-8) and miR-181b-5p to induce NETs was weaker than that of IL-8 alone. Moreover, DEK overexpression led to excessive mitochondrial dysfunction, including DRP1 up-regulation, p-DRP1ser637 and MFN2 down-regulation, mitochondrial membrane potential loss, excessive mtROS generation and mitochondrial incompleteness. Interestingly, all these phenotypes were rescued by Wnt inhibitor DKK-1 and miR-181b-5p agomir. Additionally, inhibition of DRP1 with Mdivi-1 decreased MMP-9 on BEAS-2B cells. Overall, miR-181b-5p could attenuate neutrophilic asthma through inhibition of NETs release, DEK/p-GSK-3ßSer9/ß-catenin/MMP-9 pathway, DEK/Wnt/DRP1/MMP-9 and mitochondria damage. It may become a new therapeutic target for neutrophilic asthma.
Asunto(s)
Asma , MicroARNs , Proteínas de Unión a Poli-ADP-Ribosa , Animales , Humanos , Ratones , Asma/metabolismo , beta Catenina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Inflamación/metabolismo , Interleucina-8/metabolismo , Ligandos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Bronchial asthma poses a considerable burden on both individual patients and public health. Sesamin is a natural lignan that relieves asthma. However, the potential regulatory mechanism has not been fully validated. In this study, we revealed the mechanism of sesamin in inhibiting airway inflammation of asthma. In cockroach extract (CRE)-induced asthmatic mice, sesamin efficiently inhibited inflammatory cell infiltration, expressions of total and CRE-specific IgE in serum, and inflammatory cytokines (including IL-4, 5, 13) in bronchoalveolar lavage fluid. Further study revealed that sesamin inhibited Th2 cells in the mediastinal lymph nodes and spleen, the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin, and apoptosis of lung airway epithelial cells. In vitro, sesamin had no significant cytotoxicity to BEAS-2B cells. Sesamin significantly increased TNF-α/IL-4-induced superoxide dismutase (SOD), catalase (CAT), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 related factor 2 (Nrf2), and decreased malondialdehyde. Sesamin also inhibited TNF-α/IL-4-induced mitochondrial reactive oxygen species, increased mitochondrial membrane potential, and reduced cell apoptosis as well as PINK1/Parkin expression and translocation to mitochondria. Conclusively, sesamin may relieve asthma airway inflammation by inhibiting mitophagy and mitochondrial apoptosis. Thus, sesamin may become a potential therapeutic agent for asthma.